Résumé :
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Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising as result of mutations in different NMJ proteins. CMS are a very heterogeneous group of disorders; at present, mutations in more than 10 different genes have been connected to CMS. Despite tremendous progress in recent years in understanding the molecular background of CMS some forms of CMS are still not resolved at molecular level. Until very recently, one of these unresolved CMS subgroups were the limb-girdle congenital CMS (LG-CMS), a distinct clinical variant of CMS characterised by accentuated weakness of limb muscles, but sparing of ocular or facial muscles. In this presentation the clinical phenotype and the genetic background of LG-CMS will be described.First, recessive mutations of the DOK7 gene were discovered in 2006 as cause of disease in many the patients with LG-CMS. The Dok-7 protein has been described as novel interaction partner of the musclespecific kinase MuSK at the NMJ. Disease course in many DOK7 patients was severe and progressive, often with considerable impairment of respiratory function. LG-CMS patients that did turn out to carry mutations in the DOK7 gene did not respond to a long-term treatment with esterase inhibitors, but some benefit from ephedrine was reported by us and others.LG-CMS patients that responded well to treatment with esterase inhibitors were negative for pathological changes in the DOK7 gene. The genetic basis of their disease was unknown until very recently, when we were able to map the disease locus to a 5.92 Mb region on chromosome 2. Subsequently, we identified mutations in the GFAT1/GFPT1 gene encoding the glucosamine-fructose-6-phosphate aminotransferase 1 enzyme. At present we have characterised 22 patients from 13 families in our cohort with pyridostigmine responsive LG-CMS. Many of the patients have tubular aggregates in their muscle biopsies, a finding never associated with DOK7 LG-CMS or any other CMS form. All families show an autosomal recessive disease inheritance pattern. All patients have proximal limb-girdle weakness, but neither ophthalmoparesis nor bulbar weakness. Intriguingly, GFAT1 is not selectively expressed at the NMJ like other CMS genes; it is currently unclear how defects in GFAT1 cause a NMJ disorder.
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